Roles of intracellular calcium and NF-kappaB in the Bacillus Calmette-Guérin-induced secretion of interleukin-8 from human monocytes

Cell Immunol. 2001 Aug 1;211(2):113-22. doi: 10.1006/cimm.2001.1816.

Abstract

Interleukin (IL)-8 secretion contributes to the early host response against mycobacterial infection by increasing local inflammation and recruiting professional phagocytes. Because the mechanisms through which Mycobacterium bovis Calmette-Guérin (BCG) induces IL-8 secretion are unknown, the aim of the present study was to characterize the nature of IL-8 production induced by BCG in human monocytes. In this study, we found that the induction of IL-8 synthesis was dose- and time-dependent after stimulation with BCG. This IL-8 secretion was not attributed to LPS contamination or the presence of TNF-alpha. We also determined that BCG-induced IL-8 secretion occurs through a mechanism that requires intracellular calcium and likely involves a calmodulin-sensitive step. Interestingly, BCG-induced secretion of IL-8 from human monocytes resulted from transcriptional up-regulation of the IL-8 gene. Moreover, we present evidence that BCG activates nuclear translocation of the transcription factor NF-kappaB, since pretreatment of monocytes with sulfasalazine, a inhibitor of NF-kappaB activity, blocked the ability of BCG to induce IL-8 secretion in a dose-dependent manner, producing 92.5% inhibition at a concentration of 2 mM. These results were further supported by the fact that treatment of cells with curcumin, another well-described inhibitor of NF-kappaB activity with a different mechanism of action, significantly diminished the effect of BCG on IL-8 secretion. Together, these studies are the first to demonstrate that BCG-induced IL-8 secretion by human monocytes appears to be mediated by intracellular Ca(2+) and is NF-kappaB-dependent and at the same time suggest that production of IL-8 in response to M. bovis BCG can contribute to the initial local and systemic inflammatory response in human tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / immunology*
  • Calmodulin / immunology
  • Cells, Cultured
  • Humans
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism*
  • Intracellular Fluid / metabolism
  • Monocytes / cytology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Mycobacterium bovis / immunology*
  • NF-kappa B / immunology*
  • Transcription, Genetic
  • Up-Regulation

Substances

  • Calmodulin
  • Interleukin-8
  • NF-kappa B
  • Calcium